KR100304224B1 - Rectifier dialysis machine, bioreactor and membrane - Google Patents

Abstract

The present invention provides a double skin membrane useful as a one- or rectified membrane that reduces backfiltration of solute molecules upon dialysis and improves nutrient supply and material recovery in the membrane bioreactor. Preferred as this membrane are double skin polymers in the form of hollow fibers. This membrane has polymer skins with different permeability and quarter count properties for the solute on the opposite side. The skin on each face has invisible pores at 10,000x magnification, and the microporous structure between the skins can hold solutes in the molecular weight range of about 5,000 to 200,000 at increased concentrations between the inner skin and the outer skin. Contains pores. An improved dialysis apparatus is produced by using hollow fiber membrane bundles as a dialysis means with rectifying properties.

Description

[Name]

Rectifier dialysis machine, bioreactor and membrane

[Field of Invention]

The present invention relates to fluid filtration devices such as hemodialysis devices and bioreactors and membranes for use in such devices. More specifically, the present invention relates to an improved dialysis apparatus having rectifying filtration characteristics, a dual skin membrane for carrying out such dialysis and other filtration procedures. This application is a partial continuing application of co-pending US patent application Ser. No. 07 / 818,851, filed January 10, 1992.

[Background of invention]

Dialysis membrane devices perform important life support functions when used in artificial kidneys and other types of filtration devices. For high flux dialysers, a well known problem is that undesirable molecules are backfiltered from the dialysate into the blood. Due to the high cost associated with the use of sterile dialysate without pyrogen, there is a great need for a useful dialysis membrane that can remove relatively large solutes such as β-2 microglobulins while preventing similar sized molecules from passing through the dialysate into the blood. have. However, a membrane that has a fast diffusion rate from blood to dialysate to the solute has the disadvantage that the reverse counting rate of the solute from the dialysate to the blood is also fast. Likewise, existing membranes that provide fast convection rates have the drawback that the rate of reverse filtration is also fast. Therefore, there is a need for a dialysis membrane that properly removes the uremia toxin from the blood and prevents the undesirable transfer of undesirable substances into the blood. Likewise, other fluid filtration procedures benefit from the availability of membranes having these rectification properties.

In addition, bioreactors provide a means for transporting products and waste by-products from living cells used to simultaneously produce nutrients and products that cannot be economically manufactured by traditional synthetic chemistry techniques. There has been a need for an apparatus.

[Summary of invention]

An important object of the present invention is to provide new and improved membranes for filtration devices such as dialysis devices. Another feature of the present invention provides an improved filtration device having rectification properties, ie, a sieving coefficient in one direction, which is larger than that in the other direction, and an improved filtration method using such a device. It is.

More important features of the present invention include providing a double skin membrane, such as hollow fibers, wherein the pore size and structure, and the quadrant coefficients obtained, differ between the two opposing surfaces of the membrane. In a preferred embodiment, the membrane is in the form of hollow fibers, wherein the permeability of the inner wall or skin of the fiber or the permeability to molecules of a particular size is greater than that of the outer wall. These fibers can be assembled in a dialysis device in a known manner to provide such a dialysis device capable of removing large solutes from filtrate or dialysis fluid surrounding the fiber from a fluid such as blood flowing through the interior of the fiber. Since the outside of the fiber is provided with a denser or less permeable skin, the backfeed from the outside of the fiber to the inside is substantially reduced.

Another important object of the present invention is to provide a double-skin membrane useful in dialysis as a one-way or rectifying membrane with reduced back filtration. Preferred membranes are in the form of double skin hollow fibers of polymeric material. This membrane has polymer skins with different solute permeability or quarter count characteristics on the opposite side. These membranes can be formed by compressing a polymer dissolved in a solvent while contacting at least one surface with a non-solvent for the polymer that is miscible with the solvent. In addition, the other surface is in contact with the non-payment but it is different from the first non-payment or contains a soluble additive that changes the pore size and the structure of the skin formed on the melt extruded polymer.

As another feature of the present invention, an improved permeable device having rectifying properties is made using the membrane provided by the present invention. Preferred dialysis devices of the present invention are made from hollow polymeric fiber membranes having a microporous structure in the walls of the fibrous membrane, wherein the polyporous structure has a polymer skin containing invisible pores in which the inner and outer surfaces are integrally formed. The outer skin has a different quadrant than the inner skin. The rectifying dialysis apparatus of the present invention provides a means for removing unwanted substances from body fluids such as blood, wherein a high filtration rate of the solute from the blood to the dialysate is provided, while from the dialysate of the undesired solute to the blood The rate of reverse filtration is kept substantially lower.

[drawing]

The invention will be further described with reference to the following detailed description and accompanying drawings.

1 is a diagram showing a process for producing the membrane of the present invention in the form of hollow fibers,

2 is a cross sectional view of an annular extrusion die used to carry out the invention,

3 is a side perspective view showing a partial cross section of the filtration apparatus of the present invention,

4 is a large enlarged view illustrating assuming a mechanism of filtration occurring when using the filtration device of the present invention,

5 and 6 are cross-sectional views of the hollow fiber membrane of the present invention taken at different magnification with an electron microscope,

7 is a side perspective view of a bioreactor device according to the present invention,

8-14 are graphs of the results obtained from tests in certain implementations described herein.

Referring to the drawings in greater detail, FIG. 1 shows a hollow fiber spinning system 60. The polymer solution 62 in the organic solvent is contained in the vessel 64, from which it is pumped to the annular extrusion die 68 using a metering pump 66. Likewise, the coagulant solution 72, which is a non-solvent for the polymer, is contained in the second vessel 70 and is transferred to the die 68 by another pump 74.

The interaction of the nonconductor 72 and the polymer 62 at the interface 63 formed in contact with each other as the solutions exited the die determined the final structure and properties of the inner film.

The formed compact then falls through the air gap 76 and enters the bath 78 containing the second non-coagulant coagulant solution 80. The interaction of the second solution 80 with the extrudate determines the structure and properties of the outer membrane. The fibers are pulled through the bath 78 by the driver roller 82 and, if necessary, through one or more additional baths 84 to completely extract the solvent from the hollow fibers. The extracted fibers are finally wound up on the multifaceted failure 86 and dried. The dried fibers 88 are cut to length and placed in the housing 90. Fiber 88 is sealed using thermosetting resin 92 in the housing. The assembly is closed with end caps 94 and 96. Filtrate inlet 97 and outlet 98 are also supplied on the housing.

5 and 6 are enlarged cross-sectional views of representative fibers 88 of the present invention showing inner microporous structure 83, inner skin 85, and outer skin 87 having a different porosity than inner skin 85. FIGS. . The membranes of the present invention preferably have an inner diameter of about 200 microns and generally a diameter range of about 100-1000 microns.

The total quadrant is the fraction of solute obtained through the membrane with the fluid being filtered. This is calculated by dividing the concentration of the solute on the downstream side of the membrane by the concentration on the upstream side of the membrane.

In the case of a single skin membrane, the total quadrant coefficient is equal to the quadrant coefficient of the skin, which is the fraction of solute passing through the skin. The quadrant coefficient of the skin itself depends only on the relative size of the pore and solute molecules. The denser the skin (i.e. the smaller the pore), the smaller the fraction of a given molecule passing through the skin.

However, in the case of dual skin membranes, the total quadrant coefficient is a function of both flow and membrane properties since the concentration of solute reaching the second skin depends not only on the properties of the first skin but also on the flow conditions. An important point for rectifying membranes where the quarter count in one direction is different from the quarter count in the other direction is that solute formation in the two skins of the membrane is caused by flow in one direction.

4 is a schematic of a double skin rectifying membrane 88 in which the outer skin 12 is denser than the inner skin 14 and fluid flows from the inside to the outside as a result of the imposed pressure gradient. In this case, some of the molecules entering the central region 16 of the membrane 88 will reach and be caught by the denser outer skin 12. The concentration inside the membrane increases until a steady state value is reached, with which the concentration formed in the fluid 20 outside the fiber increases. The concentration in the fiber lumen 18 did not change, therefore the total quadrant coefficient increases with time until a steady state value is reached than that obtained with the dense skin 12 alone.

When the same membrane is exposed to a pressure gradient from the opposite direction of flow from the outside to the inside, the solute cannot enter the membrane at all and there is no accumulation in the membrane. In this case both the concentration inside the membrane and the downstream concentration of the membrane are low and the total quadrant is smaller than that obtained in the other direction.

Various polymers can be used in the process of the present invention for forming hollow fibers. The polymer should be soluble in at least one organic solvent and insoluble in other liquids that are miscible with the solvent. Examples of suitable polymers are polysulfones, polyetherimides, polyacrylonitriles, polyamides, polyvinylidene difluorides, polypropylenes and polyethersulfones. Examples of such polymer solvents include N-methyl-2-pyrrolidone, N, N'-dimethylformamide, N, N'-dimethylacetamide and γ-butyrolactone. Preferred cost agents that can be used as a solidifying or gelling agent for skin formation are water. Other suitable liquids are methanol, ethanol-water mixtures such as 95 or 99.5 vol% ethanol in water, or isopropyl alcohol. Various materials can be added to the non-solvent to produce skins with different porosities. For example, polyvinyl alcohol, tetra-ethylene-glycol, poly-ethylene-glycol, perchlorate salt and polyvinyl pyrrolidone.

An important advantage of the present invention is the ability to provide fibers with different quadrature coefficients for the molecules with respect to the flow direction of the filtrate in filtering the liquid. A further advantage is the ability to provide fibers with different quadrant coefficients for filtration from liquids of molecules having a narrowly defined molecular weight range. For example, fibers can be provided that have the ability to filter molecules in the 5,000 to 10,000 molecular weight range from one side of the membrane to the other. By varying the porosity as appropriate, the quarter derivative can also be optimized for molecules having a molecular weight range of 10,000 to 100,000 or even 200,000. In addition to adjusting the composition of the coagulant solution and the amount and type of dopant added, it can be optimized by varying spinning conditions such as flow rate, linear velocity and gap distance.

EXAMPLE

The following examples illustrate the preferred methods of making and using membranes in accordance with the present invention. Unless otherwise stated, parts are all based on weight.

Example 1

Hollow fibers were prepared under the preparation and processing conditions shown in Table I using the spinning cyste and methods shown in FIGS.

[Test process]

The test modules were assembled by placing 100 fibers into a mini catapult container of about 22 cm in length and about 0.6 cm in inner diameter. Polyurethane potting extended about 1 cm from each hedo leaving about 20 cm of active length. The dialysate outlet was located about 1 cm at each end from the potting material.

Standard dialysates of the following compositions were prepared from concentrates using a hemodialyzer conditioning system.

Sodium 134 mEq / 1,

Potassium 2.6 mEq / 1,

Calcium 2.5 mEq / 1,

Magnesium 1.5 mEq / 1,

Chloride 104 mEq / 1,

Acetate 36.6 mEq / 1,

Dextrose 2500 mEq / 1,

Myoglobin solution was prepared by adding 330 mg of myoglobin per liter of dialysate. Myoglobin (molecular weight-17,000) can be measured spectrophotometrically and is therefore used as a marker for intermediate molecules such as β-2 microglobulin (molecular weight = 12,000).

The alcohol (isopropanol or ethanol) was primed using a syringe in the lumen and filtrate compartments. The test module was then rinsed with excess dialysate and pumped 250 ml through the lumen with the filtrate outlet closed, then one filtrate outlet was opened and another 200 ml was pumped. The dialysate outlet was closed to measure the flow rate of the inlet, the infusion pump was set to the desired rate (10.5 ml / min), and the outlet flow was collected and measured at time.

For quarter count measurements, the test module was clamped with the forceps so that the fibers were positioned perpendicular to the table top. The infusion pump was connected to the inlet reservoir and the tube from the infusion pump was connected to the bottom header. The tube to waste was connected to the header government. The dialysate outlet was trapped, the pump was turned on, and the time for the test solution to reach the device was zero time.

At zero time, both dialysate taps were opened to drain the priming solution on the dialysate side. The bottom dialysate outlet was then closed and a zero hour filtrate sample was taken from the top outlet as soon as the filtrate compartment was filled. At the same time, the discharge lumen sample was collected in another beaker. Influent lumen samples were taken directly from the inlet reservoir. The following filtrate samples were collected at three minute intervals with no loss of filtrate between sampling. Measurements were made on the myoglobin content of all samples using a Gilford spectrometer. The quadrant coefficient (S) was calculated using the following equation.

Sampling was continued until the calculated quadrant was constant for three consecutive samples.

The fibers were assembled into a test module and the quarter count was measured according to the procedure described above. The quadrant coefficient for myoglobin of this example fiber was found to be 0.35 when the filtrate flow was radially outward and 0.80 when the filtrate flow was inward.

TABLE 1

Polymer ........................... Polysulfone

Solvent ............... N-methylpyrrolidone

Spinning solution concentration ... 15 g / 100 g

Core Fluid Composition ... 15/85 2-Propanol / Water

Precipitation Tank Composition ......... 2/98 2-Propanol / Water

Washing tub composition ...

Gap Distance ......................... 1cm

Line Speed ........... 18 m / min

Spinning solution flow rate ... 1.8 cc / min

Core Fluid Pin Diameter .................. 0.0229 cm (0.009 in)

Annular die gap .................................. 0.00889 cm (0.0035 inches)

Example 2

Hollow fibers were prepared as in Example 1 except that the core fluid composition was 10/90 2-propanol / water and the precipitation tank composition was 5/95 2-propanol / water. 5 and 6 are scanning electron micrographs taken 2000 times and 400 times, respectively, of the resulting fiber cross-section showing the finger-like structure extending from each boundary and meeting at the intermediate wall. The quadrant coefficient for myoglobin was found to be 0.45 for the outward filtrate and 0.90 for the inward flow.

Example 3

A hollow oil was prepared as in Example 1 except that the core fluid composition was 70% isopropyl alcohol and 30% water. The concentration of the spinning solution was 20% by weight polysulfone in N-methylpyrrolidone containing 10% acetone. The settling tank was water. The quarter count of the text column was measured using the following method.

1) Text Quarter Factor

A dextran solution of the following composition was prepared in phosphate buffered saline (0.9%).

Dextran FP1 (Serva) 0.2 g / 1,

Dextran 4 (Serva) 1.0 g / 1,

Dextran T40 (Serva) 1.0 g / 1,

Dextran T10 (Serva) 0.3 g / 1.

Textlan solution was perfused through the lumen using filtrate collected from the skin side. In addition, the Textran solution was perfused through the skin side using filtrate collected from the lumen. The test sequence was changed. The flow rate of the solution was 5 ml / min and the transmembrane pressure was 150 to 200 mm Hg. Inlet lumen samples were taken directly from the dextran solution reservoir. Filtrate samples were taken at 5 minute intervals. After 15 minutes the concentration value of the filtrate was stabilized. The quadrant counts were calculated using the concentration values of the filtrate at 40 or 60 minutes. The concentration of the bulk solution was assumed to be equal to its inflow value and constant over the length of the dialyzer. Samples were analyzed by high performance liquid chromatography (HPLC) using a refractive index detector.

The results are shown in FIG.

Quadrant counts of alcohol dehydrogenase (molecular weight about 150,000) and β-amylase (molecular weight about 200,000) were determined by the method described above using samples analyzed by commercial assay kits (Sigma Chemical C.). Measured. The quarter count of alcohol dehydrogenase was 0.05 in the outward flow and 0.76 in the inward flow. The quarter count of β-amylase was 0.01 for outward flow and 0.17 for inward flow.

Example 4

Hollow fibers were prepared as in Example 1 except that the core fluid composition was 50% isopropyl alcohol and 50% water. The spinning solution contained N-methylpyrrolidone containing 20% by weight polysulfone and 10% acetone. The settling tank was water. Textan quadrant coefficients were measured from the lumen to the sheath and from the shell to the lumen. The results are shown in FIG.

Example 5

Hollow fibers were prepared as in Example 1 except that the core fluid composition was isopropyl alcohol. The spinning solution was 15% by weight of polysulfone and further 15% by weight of polyvinylpyrrolidone in N-methylpyrrolidone. The core fluid composition was isopropyl alcohol and the settling bath was water. Dextran's quadrant coefficient was measured in the same manner as in Example 3, and the results are shown in FIG.

Example 6

Polysulfone hollow fiber membranes were prepared with an outer skin having a nominal molecular weight (MW) block of 5,000 kilodaltons (kD) and a skin with a larger or unknown molecular weight block on the inner fiber surface. In these fibers, the quadrant coefficients of various molecular weights of dextran were greater in the radial inward direction than in the filtrate flow outward.

[Quarter Coefficient of Protein]

The following proteins were dissolved in phosphate buffered saline (0.9%).

Solution 1

Bovine serum albumin 2.0 g / l

Solution 2

Ovalbubin (egg albumin) 1.0 g / l

Solution 3

Myoglobin 0.08 g / l

Solution 4

Cytochrome c 0.12 g / l

The protein solution was perfused through the lumen using filtrate collected from the skin side. In addition, the protein solution was perfused through the skin side using filtrate collected from the lumen. The test sequence was changed. The incoming sample was taken directly from the protein solution reservoir. Filtrate samples were taken at 5 minute intervals. After 15 minutes the concentration value of the filtrate was stabilized. The quadrant counts were calculated using the concentration values of the filtrate at 40 or 60 minutes. The concentration of the bulk solution was assumed to be equal to its inflow value and constant over the length of the dialyzer. A spectrophotometer was used to analyze the absorbance of the sample at a particular wavelength. Bovine serum albumin and ovalbumin were analyzed at 280 nm. Myoglobin and stochrome c were analyzed at 410 nm. Fig. 11 shows the results of the quarter count test for both the text field and the monolayer by the method described above.

Example 7

Hollow fibers were prepared using the following materials according to the method of Example 1.

Polymer: Polyetherimide,

Solvent: N-methylpyrrolidone,

Concentration of spinning solution: 20% by weight,

Core fluid composition: water,

Sedimentation tank: water.

The quadrant coefficients of the tested text fields are shown in FIG.

Example 8

Hollow fibers were prepared according to the method of Example 1 using the following materials.

Polymer: Polyetherimide,

Solvent: N-methylpyrrolidone,

Concentration of spinning solution: 25% by weight,

Core Fluid Composition: 50/50 Water / N-Methylpyrrolidone,

Sedimentation tank: water.

The quarter count of the text field is shown in FIG. 13 below.

Example 9

According to current theories on the behavior of the rectifying membrane, the cause of the asymmetric quadrant characteristic of this embodiment is the internal concentration polarization of the solute. Accumulation of solutes between the two skins of the membrane should take a certain amount of production time. As a result, the quadrant coefficient should increase in one direction in time until equilibrium is reached. For most conventional membranes, the quadrant coefficient is generally the largest in early time measurements, and may decrease over time because retained solutes adhere to the pores.

In Figure 14 the quadrant coefficient from the sheath to the lumen direction is shown as a function of time for the membrane of Example 3. The filtrate was collected at 1 minute intervals in the first 10 minutes of filtration in this experiment. Over time, the quadrant coefficient increased significantly, particularly in the range of 50,000 to 100,000.

The bioreactor of the present invention consists of a device that is somewhat similar to the dialysis device shown in FIG. 7 and shown in FIG. In this case, however, the space 89 surrounding the fibers and embedded within the housing 90 and the thermosetting resin 92 forms a reaction vessel for the growth of viable cells. Outlets 97 and 98 may be omitted or closed using valves 99 and 100 as shown. Depending on the size of the product, the product may pass back through the membrane 88 to be purified from the waste stream or may be collected in an envelope space that constitutes a reaction vessel that can be removed semi-continuously or batchwise.

Transmembrane transport of nutrients, wastes and desired biological products can be by dispersion and / or convection. The axial pressure drop occurring in the hollow fiber induces Starling flow by convection from the tube side to the sheath at the inlet of the device and from the sheath to the tube at the outlet of the device.

Some types of cells require expensive growth media that can contain 10% fetal calf serum. After passing the serum component through the rectifying membrane into the cells, the volume of media required is reduced by concentrating in the envelope space. It also reduces the cost of purifying the product passing through the membrane because the volume of the refinery is smaller.

In addition, the rectifying membrane can be used to directly concentrate the product. If the desired product is formed of molecules larger than nutrients as well as metabolic waste, the rectifier membrane device reaches the cells and washes away the waste by the fluid flow passing through the interior of the hollow fiber membrane, while It can be used to concentrate the product.

Thus, the membrane according to the present invention can be formed with a denser skin on the inside or outside of the hollow membrane. In either case, it is important that the skin on each side of the membrane contain pores that are invisible at 10,000 magnification. This will result in a sufficiently dense skin on each side of the membrane, leading to the accumulation of solutes within the microporous interior of the membrane between the skins. Such accumulation of solutes is believed to be important for the construction of membranes that provide different quadrant coefficients for flow through the membrane in different directions.

Claims (14)

A plurality of double skin hollow polymer membranes, a fluid inlet means in communication with the interior of the membrane in fluid flow, an outlet means in fluid communication with the other end of the membrane for outflow of the fluid, and a generally closed and surviving cell An opening for fluid introduction into and removal of fluid from within the bioreaction vessel for growth, wherein the double skin hollow polymer membrane has a microporous structure between its walls, the midporous structure having its inner surface and outer surface With this integrally formed polymer skin, this mid-porous structure contains pores capable of maintaining a solute having a molecular weight range of 5,000 to 200,000 at an increased concentration between the inner skin and the outer skin, the membrane having a molecular weight of For fluids containing solutes containing molecules to pass in one direction through the membrane The total quadrant coefficient and the total quadrant coefficient for the fluid passing through the membrane in opposite directions are different, and the hollow polymer membrane is fixed in a totally parallel direction within the enclosure, the Opposite ends are made of a polymer resin encapsulating the exterior of the fiber, opposing ends of the fiber extend through the polymeric resin, and the exterior of the fiber and the interior of the closed vessel define the bioreaction vessel. Bioreactor. A plurality of double skin hollow polymer membranes, a fluid inlet means in communication with the interior of the membrane in fluid flow, an outlet means in fluid communication with the other end of the membrane for outflow of the fluid, and a hermetically sealed and viable growth cell An opening for fluid introduction into and removal of fluid from within the bioreaction vessel, wherein the double skin hollow polymer membrane has a microporous structure between its walls, the microporous structure having an inner surface and an outer surface thereof integrally. And having a polymer skin formed, the microporous structure contains pores capable of maintaining an increased concentration between the inner skin and the outer skin of the solute having a molecular weight range of 5,000 to 200,000, and the membrane contains molecules of the molecular weight range. Total loss of fluid containing the containing solute in one direction through the membrane The fraction coefficient and the total quadrant coefficient for the fluid passing through the membrane in opposite directions are different, and the hollow polymer membrane is fixed in a totally parallel direction in the hermetic container, and opposite ends of the hermetic container have the fiber encapsulated outside. Wherein the opposite ends of the fiber extend through the polymer resin and wherein the exterior of the fiber and the interior of the closed vessel define the bioreaction vessel. A fluid containing nutrients for said cells is flowed through said hollow membrane to transfer said nutrients through said membrane to said cells and to remove waste from said cells as said waste is transferred to said fluid through said membrane. To remove biological products from the vessel A method for producing a biological product comprising. Has a microporous structure in its walls that has a polymer skin formed integrally with its inner and outer surfaces, the skin on each surface having pores invisible at 10,000 magnifications, said skin between said skins The microporous structure contains pores capable of maintaining a solute having a molecular weight range of 5,000 to 200,000 at an increased concentration between the inner skin and the outer skin, and fluids containing solutes containing molecules in the molecular weight range may contain the membrane. A double skin hollow polymer membrane having a total quadrant coefficient for passing in one direction through and a total quadrant coefficient for passing the membrane in the opposite direction. The membrane of claim 3 comprising hollow polysulfone fibers. The membrane of claim 3, wherein the skin on the inner surface of the hollow membrane is less restrictive for the passage of the solute than the skin on the outer surface. The membrane of claim 3, wherein the skin on the outer surface of the hollow membrane is less restrictive to the passage of the solute than the skin on the inner surface. The membrane of claim 3 comprising hollow polyetherimide fibers. The membrane of claim 5 having an inner diameter of 100 to 1000 μ. Within its walls there is a microporous structure, the microporous structure having a polymer skin integrally formed with its inner and outer surfaces, each of which can move solute molecules having a molecular weight range of 5,000 to 200,000 through the membrane. However, when a liquid containing such a solute is filtered through the membrane from the looser side of the skin to the denser side of the skin, it sufficiently restricts such migration leading to an increase in the concentration of the molecule in the microporous structure. The total quadrant coefficient of the membrane for passage of the fluid in one direction through the membrane with a fluid containing a solute containing molecules in the molecular weight range, having an invisible pore at 10,000 magnifications of size and structure, and the fluid in the opposite direction. Among double skin hollows with different total quadrant coefficients for passing through the membrane Sieve membrane. 10. The membrane of claim 9 comprising a polysulfone polymer. The membrane of claim 10, wherein one of the skins has a different quadrant for molecules of molecular weight of 10,000 to 20,000 compared to the other skins. A plurality of double skin hollow polymer membranes, first fluid inlet means in fluid communication with the interior of the membrane, outlet means in fluid communication with the other end of the membrane for outflow of the first fluid, and the interior of the hermetically sealed container And a fluid flow passage comprising inflow and outflow passages in communication with the fluid flow and flowing a second fluid to contact the outer surface of the membrane, wherein the double skin hollow polymer membrane is secured in a substantially parallel direction within the hermetic container. Has a microporous structure in its walls, the microporous structure having a polymer skin formed integrally with its inner surface and outer surface, each skin containing microcellular fish invisible at 10,000 magnifications, the membrane having 5,000 A liquid containing a solute having a molecular weight ranging from 200,000 to 200,000 is passed through the membrane in one direction. The quadrant coefficient for fluid passing through the membrane in the opposite direction is the same as the quadrant coefficient for discharging, and the flow passage of the second fluid communicates with the fluid flow with the interior of the hermetic container to flow the dialysate to the outer surface of the membrane Inlet and outlet passages, the opposing ends of the hermetically sealed container made of a polymer resin encapsulating the outside of the fiber, the opposing ends of the fiber extending through the polymer resin Device. 13. The apparatus of claim 12, wherein the quadrant coefficient for the molecule is greater in the passage from the outside to the interior than the passage from the inside of the fiber to the outside. 13. The apparatus of claim 12 wherein the quarter count for the molecule is greater in the passage from the inside to the outside than the passage of the fibers from the outside to the inside.